rs387906485

Variant names:

• chrX-37783600-G-A
• rs387906485
• NM_000397.4:c.252G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-37783600-G-A
• chrX-37783600-G-C
• chrX-37783600-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000397.4(CYBB):​c.252G>A​(p.Ala84Ala) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CYBB NM_000397.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.49

Genes affected

CYBB (HGNC:2578): (cytochrome b-245 beta chain) Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes. CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole. [provided by RefSeq, Jul 2008]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-37783600-G-A is Pathogenic according to our data. Variant chrX-37783600-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-37783600-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4	c.252G>A	p.Ala84Ala	splice_region_variant, synonymous_variant	Exon 3 of 13	ENST00000378588.5	NP_000388.2
CYBB	XM_047441855.1	c.-179G>A		splice_region_variant	Exon 1 of 12		XP_047297811.1
CYBB	XM_047441855.1	c.-179G>A		5_prime_UTR_variant	Exon 1 of 12		XP_047297811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.252G>A	p.Ala84Ala	splice_region_variant, synonymous_variant	Exon 3 of 13	1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	c.171+357600G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1046026 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 318182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Mar 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the variant results in the skipping of exon 3 and a minor fraction of mRNA expression (Ishibashi et al., 2001; Khaldi et al., 2009; Hui et al., 1996); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19483051, 25525159, 22929960, 10914676, 9585602, 8916969, 8900212, 32712647, 18546332, 33717137, 35140711, 22015033, 11435314, 8634410, 17543165, 15577746, 29560547, 23193493, 33325540, 30470980, 32084423, 31375816, 35874699, 34206017, 34175765) -

May 12, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CYBB: PVS1:Strong, PP1:Moderate, PS4:Moderate, PM2:Supporting, PS1:Supporting -

Granulomatous disease, chronic, X-linked Pathogenic:3

Jun 21, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CYBB c.252G>A (p.Ala84Ala) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5 splicing donor site. Three predict the variant weakens a 5' donor site. Publications also reported experimental evidence that this variant affects mRNA splicing, demonstrating partial exon 3 skipping (Ishibashi 2000, Khaldi 2009). The variant was absent in 84096 control chromosomes. c.252G>A has been reported in the literature in multiple individuals affected with X-linked Chronic Granulomatous Disease (Rae 1998, Ishibashi 2000), however in several cases with a less severe, atypical or heterogeneous phenotypes (Khaldi 2009, Gutierrez 2012). These data indicate that the variant is very likely to be associated with disease. Several publications also reported experimental evidence evaluating an impact on protein function, demonstrating a residual NADPH oxidase activity and an abnormal neutrophil oxidative burst (e.g. Rae 1998, Gutierrez 2012). The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

May 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 84 of the CYBB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CYBB protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with chronic granulomatous disease (PMID: 8634410, 11435314, 18546332, 29560547, 30470980). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10933). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exons 2-3, but is expected to preserve the integrity of the reading-frame (PMID: 11435314). For these reasons, this variant has been classified as Pathogenic. -

Granulomatous disease, chronic, X-linked;C1970859:X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency Pathogenic:1

Sep 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.77		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906485; hg19: chrX-37642853;